Safety and Efficacy of Desensitization Therapy in Sensitized Participants Awaiting Heart Transplantation

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT01769443
• Collaborator: Clinical Trials in Organ Transplantation (Other)
• Enrollment: 2
• Locations: 14
• Arms: 2
• Duration (Months): 13
• Patients Per Site: 0.1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The primary objective is to evaluate the efficacy of desensitization therapy, which includes VELCADE® (bortezomib) and plasmapheresis, on select sensitized patients awaiting heart transplantation.

Condition or Disease	Intervention/Treatment	Phase
Primary Heart Transplant; Heart Transplantation; Heart Transplant	Drug: bortezomib; Procedure: plasmapheresis	Phase 2

Detailed Description

Bortezomib works by decreasing plasma cells in the blood. Plasma cells produce antibodies. Plasmapheresis is a procedure that removes antibodies from the blood. Plasma cells and antibodies produced by plasma cells can be involved in organ rejection after transplantation.

This trial will evaluate if decreasing plasma cells and antibodies with bortezomib and plasmapheresis can reduce complications while participants are waiting for their heart transplant. The evaluation of efficacy is defined by a lower complication rate while on the heart transplant waitlist.

Study Design

• Study Type: Interventional
• Actual Enrollment: 2 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Prospective, Randomized, Multicenter, Two-Parallel Arm Study Evaluating the Overall Efficacy and Safety of Desensitization Therapy on Selected Patients Awaiting Heart Transplantation
• Study Start Date: Jun 1, 2013
• Actual Primary Completion Date: Jul 1, 2014
• Actual Study Completion Date: Jul 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: No Desensitization Therapy Subject(s) randomized to no desensitization therapy pre-transplant.
Experimental: Desensitization Therapy Subject(s) randomized to desensitization therapy pre-transplant. Desensitization therapy regimen pre-transplant: Plasmapheresis for 3 consecutive days (treatment days 0, 1 and 2) followed by concomitant bortezomib dosed at 1.3 mg/m^2 as a 3 to 5 second bolus intravenous injection on treatment days 0, 3, 7 and 10. The first dose of bortezomib is administered between 4-8 hours after the first plasmapheresis session is completed and there must be at least 96 hours between the second and third dose of bortezomib.	Drug: bortezomib; Bortezomib dosed at 1.3 mg/m^2 as a 3 to 5 second bolus administered by intravenous injection on treatment days 0, 3, 7 and 10. The first dose of bortezomib is administered between 4-8 hours after the first plasmapheresis session is completed and there must be at least 96 hours between the second and third dose of bortezomib.; Other Names: VELCADE® ; Procedure: plasmapheresis; Plasmapheresis for 3 consecutive days (treatment days 0, 1 and 2) followed by concomitant bortezomib dosed at 1.3 mg/m^2 as a 3 to 5 second bolus administered by intravenous injection on treatment days 0, 3, 7 and 10. The first dose of bortezomib is administered between 4-8 hours after the first plasmapheresis session is completed and there must be at least 96 hours between the second and third dose of bortezomib.; Other Names: apheresis (plasma)

Outcome Measures

Primary Outcome Measures

1. Composite of Incidence of the Following Events in Subjects [At transplant, or 90 days post-randomization, whichever occurs first]

   Death, Removal from the transplant waiting list for any reason except improvement of cardiac function, Initiation of any mechanical circulatory support device, Severe infection requiring intravenous antibiotics, Cerebral vascular accident, Acute renal failure requiring dialysis.

Secondary Outcome Measures

1. Time From Wait Listing to Heart Transplantation [At transplant, or 1 year post-randomization, whichever occurs first]

2. Change in Calculated PRA (cPRA) From Wait Listing to Transplantation [At transplant, or 1 year post-randomization, whichever occurs first]

3. Incidence of Death [At transplant, or 1 year post-randomization, whichever occurs first]

4. Incidence of Removal From Transplant Waiting List for Any Reason Except Improvement of Cardiac Function [At transplant, or 1 year post-randomization, whichever occurs first]

5. Incidence of Initiation of Any Mechanical Circulatory Support Device [At transplant, or 1 year post-randomization, whichever occurs first]

6. Incidence of Severe Infection Requiring Intravenous Antibiotics [At transplant, or 1 year post-randomization, whichever occurs first]

7. Incidence of Cerebral Vascular Accident [At transplant, or 1 year post-randomization, whichever occurs first]

8. Incidence of Acute Renal Failure Requiring Hemodialysis [At transplant, or 1 year post-randomization, whichever occurs first]

9. Incidence of Administering Desensitization Therapy Beyond 90 Days After Randomization [At transplant, or 1 year post-randomization, whichever occurs first]

10. Development of Angiographically Evident Cardiac Allograft Vasculopathy at 1 Year [24 and 52 weeks post-transplantation]

11. Incidence of Serious Infections Requiring Intravenous Antimicrobial Therapy [24 and 52 weeks post-transplantation]

12. Number of Subjects on Left Ventricular Assist Devices (LVAD) Compared to Those Not on LVADs [24 and 52 weeks post-transplantation]

13. Cardiac Dysfunction as Reflected in the Left Ventricular Ejection Fractions < 40% by Echocardiography, Angiogram or Nuclear Testing. [24 and 52 weeks:]

14. Incidence of Post-Transplant Lymphoproliferative Disorder (PTLD) [24 and 52 weeks post-transplantation]

15. Death [24 and 52 weeks post-transplantation]

16. Re-transplantation or Re-listed for Transplantation [24 and 52 weeks post-transplantation]

17. Incidence of Hospitalizations [24 and 52 weeks post-transplantation]

18. Incidence of Rejection Episodes Per Subject and Freedom From Rejection [24 and 52 weeks post-transplantation]

    Rejection is defined as follows: Biopsy proven acute rejection (BPAR) of any grade (cellular rejection per 2004 ISHLT [International Society of Heart and Lung Transplantation] grading scale), BPAR (individual grades), BPAR (Biopsy Proven Acute Rejection) > 2R antibody mediated rejection (AMR), Any treated rejection, Rejection associated with hemodynamic compromise (HDC).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subject must be able to understand and provide informed consent;

• Candidate (as recipient) for a primary heart transplant (single organ transplant);

• Calculated panel reactive antibody (cPRA) of greater than 30% with a threshold using mean fluorescent intensity (MFI) of 3,000 or standard fluorescence intensity (SFI) of 60,000;

• Status 1 (1A or 1B) enrollment and randomization to occur within 2 weeks after status 1 listing;

• Female subject is either postmenopausal for at least 1 year before the screening visit, is surgically sterilized or if they are of childbearing potential, agree to practice 2 effective methods of contraception from the time of signing the informed consent form through 30 days after the last dose of bortezomib, or agree to completely abstain from heterosexual intercourse;

• Male subjects, even if surgically sterilized (i.e., status postvasectomy) must agree to 1 of the following: practice effective barrier contraception during the entire study treatment period and through a minimum of 30 days after the last dose of study drug, or completely abstain from heterosexual intercourse;

• Negative test for HIV (human immunodeficiency virus), HBsAg (hepatitis B surface antigen), HBcAb (hepatitis B core antibody), and HCV (hepatitis C virus) antibodies within 6 months prior to study entry.

Exclusion Criteria:

• Recipient of multiple solid organ or tissue transplants;

• Prior history of organ transplantation;

• Women of childbearing potential with a positive serum β-human chorionic gonadotropin (β-hCG) pregnancy test.Pregnancy testing is not required for postmenopausal or surgically sterilized women;

• Currently breast-feeding a child or plans to become pregnant during the timeframe of the study follow-up period;

• Subject has a hypersensitivity to VELCADE® (bortezomib), boron, or mannitol;

• Active systemic infection at time of enrollment;

• Any history of serologic positivity to HIV, HBsAg, HBcAb and HCV Ab;

• History of malignancy except when noted by an oncology specialist that tumor recurrence is low based on tumor type, response to therapy and negative metastatic work-up;

• Radiation therapy within 3 weeks before randomization. Enrollment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy;

• Subjects with a platelet count of less than 75,000 within 7 days prior to enrollment;

• Subjects with an absolute neutrophil count (ANC) of less than 1,500 within 7 days prior to enrollment;

• Subjects with >1.5 x ULN (upper limit of normal) total bilirubin;

• Subjects with any grade or history of neuropathy;

• Any condition that, in the opinion of the investigator, would interfere with the subject's ability to comply with study requirements;

• Participation in another interventional clinical trial or requiring treatment using un-marketed investigational drug(s) within 14 days of start of this trial and throughout the duration of this trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cedars Sinai Heart Institute	Beverly Hills	California	United States	90211
2	University of California at San Francisco	San Francisco	California	United States	94143
3	Yale New Haven Hospital	New Haven	Connecticut	United States	06510
4	Northwestern University Feinberg School of Medicine	Chicago	Illinois	United States	60611
5	Rush University Medical Center	Chicago	Illinois	United States	60612
6	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
7	Minneapolis Heart Institute	Minneapolis	Minnesota	United States	55407
8	Mount Sinai School of Medicine	New York	New York	United States	10029
9	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
10	Drexel University College of Medicine	Philadelphia	Pennsylvania	United States	19102
11	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
12	The Methodist Hospital	Houston	Texas	United States	77030
13	Intermountain Medical Center	Murray	Utah	United States	84157
14	University of Utah	Salt Lake City	Utah	United States	84132

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)
• Clinical Trials in Organ Transplantation

Investigators

• Study Chair: Jon A Kobashigawa, MD, Cedars-Sinai Heart Institute
• Principal Investigator: Peter S. Heeger, MD, Icahn School of Medicine at Mount Sinai

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• National Institute of Allergy and Infectious Diseases (NIAID)
• Clinical Trials in Organ Transplantation (CTOT)

Publications

• John R, Lietz K, Burke E, Ankersmit J, Mancini D, Suciu-Foca N, Edwards N, Rose E, Oz M, Itescu S. Intravenous immunoglobulin reduces anti-HLA alloreactivity and shortens waiting time to cardiac transplantation in highly sensitized left ventricular assist device recipients. Circulation. 1999 Nov 9;100(19 Suppl):II229-35.
• Jordan SC, Vo A, Bunnapradist S, Toyoda M, Peng A, Puliyanda D, Kamil E, Tyan D. Intravenous immune globulin treatment inhibits crossmatch positivity and allows for successful transplantation of incompatible organs in living-donor and cadaver recipients. Transplantation. 2003 Aug 27;76(4):631-6.
• Leech SH, Lopez-Cepero M, LeFor WM, DiChiara L, Weston M, Furukawa S, Macha M, Singhal A, Wald JW, Nikolaidis LA, McClurken JB, Bove AA. Management of the sensitized cardiac recipient: the use of plasmapheresis and intravenous immunoglobulin. Clin Transplant. 2006 Jul-Aug;20(4):476-84.
• McGee EC Jr, Cotts W, Tambur AR, Friedewald J, Kim J, O'Connell J, Wallace S, McCarthy PM. Successful bridge to transplant in a highly sensitized patient with a complicated pump pocket infection. J Heart Lung Transplant. 2008 May;27(5):568-71. doi: 10.1016/j.healun.2008.02.006.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT01769443
• Other Study ID Numbers: DAIT CTOT-13; U01AI063594
• First Posted: Jan 16, 2013
• Last Update Posted: Nov 11, 2015
• Last Verified: Oct 1, 2015

• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): desensitization therapy; bortezomib (VELCADE®); plasmapheresis
• Additional relevant MeSH terms: Bortezomib

Study Results

Participant Flow

Recruitment Details	The study planned to enroll 80 participants; however, the decision to terminate the study was made due to the very slow rate of participant accrual and the inability to meet the recruitment goal within the funding period. Only 2 participants were enrolled at one site before study recruitment status changed to "Active, not recruiting."

Arm/Group Title	No Desensitization	Desensitization
Arm/Group Description	No desensitization therapy pre-transplantation	Plasmapheresis with concomitant bortezomib. Plasmapheresis will be given for 3 consecutive days (treatment days 0, 1 and 2) within 2 weeks of Status I listing for heart transplantation. Plasmapheresis is a procedure that involves the extracorporeal separation of plasma from cellular blood components by centrifugation or membrane filtration, which removes the alloantibody. The plasma depleted blood is reconstituted with exogenous fresh-frozen plasma or albumin solution which is then infused back into the patient. Four doses of bortezomib (1.3 mg/m^2) were administered intravenously on treatment days 0, 3, 7 and 10. The first dose was given between 4-8 hours after the first plasmapheresis session was completed and there was at least 96 hours between the second and third dose of bortezomib
Period Title: Overall Study
STARTED	1	1
COMPLETED	0	1
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	No Desensitization	Desensitization	Total
Arm/Group Description	No desensitization therapy pre-transplantation	Plasmapheresis with concomitant bortezomib. Plasmapheresis will be given for 3 consecutive days (treatment days 0, 1 and 2) within 2 weeks of Status I listing for heart transplantation. Plasmapheresis is a procedure that involves the extracorporeal separation of plasma from cellular blood components by centrifugation or membrane filtration, which removes the alloantibody. The plasma depleted blood is reconstituted with exogenous fresh-frozen plasma or albumin solution which is then infused back into the patient. Four doses of bortezomib (1.3 mg/m^2) were administered intravenously on treatment days 0, 3, 7 and 10. The first dose was given between 4-8 hours after the first plasmapheresis session was completed and there was at least 96 hours between the second and third dose of bortezomib	Total of all reporting groups
Overall Participants	1	1	2
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	1 100%	0 0%	1 50%
>=65 years	0 0%	1 100%	1 50%
Sex: Female, Male (Count of Participants)
Female	1 100%	0 0%	1 50%
Male	0 0%	1 100%	1 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	1 100%	1 100%	2 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	1 100%	1 100%	2 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	1 100%	1 100%	2 100%

Outcome Measures

1. Primary Outcome

Title	Composite of Incidence of the Following Events in Subjects
Description	Death, Removal from the transplant waiting list for any reason except improvement of cardiac function, Initiation of any mechanical circulatory support device, Severe infection requiring intravenous antibiotics, Cerebral vascular accident, Acute renal failure requiring dialysis.
Time Frame	At transplant, or 90 days post-randomization, whichever occurs first

Outcome Measure Data

Analysis Population Description

No analyses were performed due to slow enrollment and early study closure.

Arm/Group Title	No Desensitization	Desensitization
Arm/Group Description	No desensitization therapy pre-transplantation	Plasmapheresis with concomitant bortezomib. Plasmapheresis will be given for 3 consecutive days (treatment days 0, 1 and 2) within 2 weeks of Status I listing for heart transplantation. Plasmapheresis is a procedure that involves the extracorporeal separation of plasma from cellular blood components by centrifugation or membrane filtration, which removes the alloantibody. The plasma depleted blood is reconstituted with exogenous fresh-frozen plasma or albumin solution which is then infused back into the patient. Four doses of bortezomib (1.3 mg/m^2) were administered intravenously on treatment days 0, 3, 7 and 10. The first dose was given between 4-8 hours after the first plasmapheresis session was completed and there was at least 96 hours between the second and third dose of bortezomib
Measure Participants	0	0

2. Secondary Outcome

Title	Time From Wait Listing to Heart Transplantation
Time Frame	At transplant, or 1 year post-randomization, whichever occurs first

Outcome Measure Data

Analysis Population Description

No analyses were performed due to slow enrollment and early study closure.

Arm/Group Title	No Desensitization	Desensitization
Arm/Group Description	No desensitization therapy pre-transplantation	Plasmapheresis with concomitant bortezomib. Plasmapheresis will be given for 3 consecutive days (treatment days 0, 1 and 2) within 2 weeks of Status I listing for heart transplantation. Plasmapheresis is a procedure that involves the extracorporeal separation of plasma from cellular blood components by centrifugation or membrane filtration, which removes the alloantibody. The plasma depleted blood is reconstituted with exogenous fresh-frozen plasma or albumin solution which is then infused back into the patient. Four doses of bortezomib (1.3 mg/m^2) were administered intravenously on treatment days 0, 3, 7 and 10. The first dose was given between 4-8 hours after the first plasmapheresis session was completed and there was at least 96 hours between the second and third dose of bortezomib
Measure Participants	0	0

3. Secondary Outcome

Title	Change in Calculated PRA (cPRA) From Wait Listing to Transplantation
Time Frame	At transplant, or 1 year post-randomization, whichever occurs first

Outcome Measure Data

Analysis Population Description

No analyses were performed due to slow enrollment and early study closure.

Arm/Group Title	No Desensitization	Desensitization
Arm/Group Description	No desensitization therapy pre-transplantation	Plasmapheresis with concomitant bortezomib. Plasmapheresis will be given for 3 consecutive days (treatment days 0, 1 and 2) within 2 weeks of Status I listing for heart transplantation. Plasmapheresis is a procedure that involves the extracorporeal separation of plasma from cellular blood components by centrifugation or membrane filtration, which removes the alloantibody. The plasma depleted blood is reconstituted with exogenous fresh-frozen plasma or albumin solution which is then infused back into the patient. Four doses of bortezomib (1.3 mg/m^2) were administered intravenously on treatment days 0, 3, 7 and 10. The first dose was given between 4-8 hours after the first plasmapheresis session was completed and there was at least 96 hours between the second and third dose of bortezomib
Measure Participants	0	0

4. Secondary Outcome

Title	Incidence of Death
Time Frame	At transplant, or 1 year post-randomization, whichever occurs first

Outcome Measure Data

Analysis Population Description

No analyses were performed due to slow enrollment and early study closure.

Arm/Group Title	No Desensitization	Desensitization
Arm/Group Description	No desensitization therapy pre-transplantation	Plasmapheresis with concomitant bortezomib. Plasmapheresis will be given for 3 consecutive days (treatment days 0, 1 and 2) within 2 weeks of Status I listing for heart transplantation. Plasmapheresis is a procedure that involves the extracorporeal separation of plasma from cellular blood components by centrifugation or membrane filtration, which removes the alloantibody. The plasma depleted blood is reconstituted with exogenous fresh-frozen plasma or albumin solution which is then infused back into the patient. Four doses of bortezomib (1.3 mg/m^2) were administered intravenously on treatment days 0, 3, 7 and 10. The first dose was given between 4-8 hours after the first plasmapheresis session was completed and there was at least 96 hours between the second and third dose of bortezomib
Measure Participants	0	0

5. Secondary Outcome

Title	Incidence of Removal From Transplant Waiting List for Any Reason Except Improvement of Cardiac Function
Time Frame	At transplant, or 1 year post-randomization, whichever occurs first

Outcome Measure Data

Analysis Population Description

No analyses were performed due to slow enrollment and early study closure.

Arm/Group Title	No Desensitization	Desensitization
Arm/Group Description	No desensitization therapy pre-transplantation	Plasmapheresis with concomitant bortezomib. Plasmapheresis will be given for 3 consecutive days (treatment days 0, 1 and 2) within 2 weeks of Status I listing for heart transplantation. Plasmapheresis is a procedure that involves the extracorporeal separation of plasma from cellular blood components by centrifugation or membrane filtration, which removes the alloantibody. The plasma depleted blood is reconstituted with exogenous fresh-frozen plasma or albumin solution which is then infused back into the patient. Four doses of bortezomib (1.3 mg/m^2) were administered intravenously on treatment days 0, 3, 7 and 10. The first dose was given between 4-8 hours after the first plasmapheresis session was completed and there was at least 96 hours between the second and third dose of bortezomib
Measure Participants	0	0

6. Secondary Outcome

Title	Incidence of Initiation of Any Mechanical Circulatory Support Device
Time Frame	At transplant, or 1 year post-randomization, whichever occurs first

Outcome Measure Data

Analysis Population Description

No analyses were performed due to slow enrollment and early study closure.

Arm/Group Title	No Desensitization	Desensitization
Arm/Group Description	No desensitization therapy pre-transplantation	Plasmapheresis with concomitant bortezomib. Plasmapheresis will be given for 3 consecutive days (treatment days 0, 1 and 2) within 2 weeks of Status I listing for heart transplantation. Plasmapheresis is a procedure that involves the extracorporeal separation of plasma from cellular blood components by centrifugation or membrane filtration, which removes the alloantibody. The plasma depleted blood is reconstituted with exogenous fresh-frozen plasma or albumin solution which is then infused back into the patient. Four doses of bortezomib (1.3 mg/m^2) were administered intravenously on treatment days 0, 3, 7 and 10. The first dose was given between 4-8 hours after the first plasmapheresis session was completed and there was at least 96 hours between the second and third dose of bortezomib
Measure Participants	0	0

7. Secondary Outcome

Title	Incidence of Severe Infection Requiring Intravenous Antibiotics
Time Frame	At transplant, or 1 year post-randomization, whichever occurs first

Outcome Measure Data

Analysis Population Description

No analyses were performed due to slow enrollment and early study closure.

Arm/Group Title	No Desensitization	Desensitization
Arm/Group Description	No desensitization therapy pre-transplantation	Plasmapheresis with concomitant bortezomib. Plasmapheresis will be given for 3 consecutive days (treatment days 0, 1 and 2) within 2 weeks of Status I listing for heart transplantation. Plasmapheresis is a procedure that involves the extracorporeal separation of plasma from cellular blood components by centrifugation or membrane filtration, which removes the alloantibody. The plasma depleted blood is reconstituted with exogenous fresh-frozen plasma or albumin solution which is then infused back into the patient. Four doses of bortezomib (1.3 mg/m^2) were administered intravenously on treatment days 0, 3, 7 and 10. The first dose was given between 4-8 hours after the first plasmapheresis session was completed and there was at least 96 hours between the second and third dose of bortezomib
Measure Participants	0	0

8. Secondary Outcome

Title	Incidence of Cerebral Vascular Accident
Time Frame	At transplant, or 1 year post-randomization, whichever occurs first

Outcome Measure Data

Analysis Population Description

No analyses were performed due to slow enrollment and early study closure.

Arm/Group Title	No Desensitization	Desensitization
Arm/Group Description	No desensitization therapy pre-transplantation	Plasmapheresis with concomitant bortezomib. Plasmapheresis will be given for 3 consecutive days (treatment days 0, 1 and 2) within 2 weeks of Status I listing for heart transplantation. Plasmapheresis is a procedure that involves the extracorporeal separation of plasma from cellular blood components by centrifugation or membrane filtration, which removes the alloantibody. The plasma depleted blood is reconstituted with exogenous fresh-frozen plasma or albumin solution which is then infused back into the patient. Four doses of bortezomib (1.3 mg/m^2) were administered intravenously on treatment days 0, 3, 7 and 10. The first dose was given between 4-8 hours after the first plasmapheresis session was completed and there was at least 96 hours between the second and third dose of bortezomib
Measure Participants	0	0

9. Secondary Outcome

Title	Incidence of Acute Renal Failure Requiring Hemodialysis
Time Frame	At transplant, or 1 year post-randomization, whichever occurs first

Outcome Measure Data

Analysis Population Description

No analyses were performed due to slow enrollment and early study closure.

Arm/Group Title	No Desensitization	Desensitization
Arm/Group Description	No desensitization therapy pre-transplantation	Plasmapheresis with concomitant bortezomib. Plasmapheresis will be given for 3 consecutive days (treatment days 0, 1 and 2) within 2 weeks of Status I listing for heart transplantation. Plasmapheresis is a procedure that involves the extracorporeal separation of plasma from cellular blood components by centrifugation or membrane filtration, which removes the alloantibody. The plasma depleted blood is reconstituted with exogenous fresh-frozen plasma or albumin solution which is then infused back into the patient. Four doses of bortezomib (1.3 mg/m^2) were administered intravenously on treatment days 0, 3, 7 and 10. The first dose was given between 4-8 hours after the first plasmapheresis session was completed and there was at least 96 hours between the second and third dose of bortezomib
Measure Participants	0	0

10. Secondary Outcome

Title	Incidence of Administering Desensitization Therapy Beyond 90 Days After Randomization
Time Frame	At transplant, or 1 year post-randomization, whichever occurs first

Outcome Measure Data

Analysis Population Description

No analyses were performed due to slow enrollment and early study closure.

Arm/Group Title	No Desensitization	Desensitization
Arm/Group Description	No desensitization therapy pre-transplantation	Plasmapheresis with concomitant bortezomib. Plasmapheresis will be given for 3 consecutive days (treatment days 0, 1 and 2) within 2 weeks of Status I listing for heart transplantation. Plasmapheresis is a procedure that involves the extracorporeal separation of plasma from cellular blood components by centrifugation or membrane filtration, which removes the alloantibody. The plasma depleted blood is reconstituted with exogenous fresh-frozen plasma or albumin solution which is then infused back into the patient. Four doses of bortezomib (1.3 mg/m^2) were administered intravenously on treatment days 0, 3, 7 and 10. The first dose was given between 4-8 hours after the first plasmapheresis session was completed and there was at least 96 hours between the second and third dose of bortezomib
Measure Participants	0	0

11. Secondary Outcome

Title	Development of Angiographically Evident Cardiac Allograft Vasculopathy at 1 Year
Time Frame	24 and 52 weeks post-transplantation

Outcome Measure Data

Analysis Population Description

No analyses were performed due to slow enrollment and early study closure.

Arm/Group Title	No Desensitization	Desensitization
Arm/Group Description	No desensitization therapy pre-transplantation	Plasmapheresis with concomitant bortezomib. Plasmapheresis will be given for 3 consecutive days (treatment days 0, 1 and 2) within 2 weeks of Status I listing for heart transplantation. Plasmapheresis is a procedure that involves the extracorporeal separation of plasma from cellular blood components by centrifugation or membrane filtration, which removes the alloantibody. The plasma depleted blood is reconstituted with exogenous fresh-frozen plasma or albumin solution which is then infused back into the patient. Four doses of bortezomib (1.3 mg/m^2) were administered intravenously on treatment days 0, 3, 7 and 10. The first dose was given between 4-8 hours after the first plasmapheresis session was completed and there was at least 96 hours between the second and third dose of bortezomib
Measure Participants	0	0

12. Secondary Outcome

Title	Incidence of Serious Infections Requiring Intravenous Antimicrobial Therapy
Time Frame	24 and 52 weeks post-transplantation

Outcome Measure Data

Analysis Population Description

No analyses were performed due to slow enrollment and early study closure.

Arm/Group Title	No Desensitization	Desensitization
Arm/Group Description	No desensitization therapy pre-transplantation	Plasmapheresis with concomitant bortezomib. Plasmapheresis will be given for 3 consecutive days (treatment days 0, 1 and 2) within 2 weeks of Status I listing for heart transplantation. Plasmapheresis is a procedure that involves the extracorporeal separation of plasma from cellular blood components by centrifugation or membrane filtration, which removes the alloantibody. The plasma depleted blood is reconstituted with exogenous fresh-frozen plasma or albumin solution which is then infused back into the patient. Four doses of bortezomib (1.3 mg/m^2) were administered intravenously on treatment days 0, 3, 7 and 10. The first dose was given between 4-8 hours after the first plasmapheresis session was completed and there was at least 96 hours between the second and third dose of bortezomib
Measure Participants	0	0

13. Secondary Outcome

Title	Number of Subjects on Left Ventricular Assist Devices (LVAD) Compared to Those Not on LVADs
Time Frame	24 and 52 weeks post-transplantation

Outcome Measure Data

Analysis Population Description

No analyses were performed due to slow enrollment and early study closure.

Arm/Group Title	No Desensitization	Desensitization
Arm/Group Description	No desensitization therapy pre-transplantation	Plasmapheresis with concomitant bortezomib. Plasmapheresis will be given for 3 consecutive days (treatment days 0, 1 and 2) within 2 weeks of Status I listing for heart transplantation. Plasmapheresis is a procedure that involves the extracorporeal separation of plasma from cellular blood components by centrifugation or membrane filtration, which removes the alloantibody. The plasma depleted blood is reconstituted with exogenous fresh-frozen plasma or albumin solution which is then infused back into the patient. Four doses of bortezomib (1.3 mg/m^2) were administered intravenously on treatment days 0, 3, 7 and 10. The first dose was given between 4-8 hours after the first plasmapheresis session was completed and there was at least 96 hours between the second and third dose of bortezomib
Measure Participants	0	0

14. Secondary Outcome

Title	Cardiac Dysfunction as Reflected in the Left Ventricular Ejection Fractions < 40% by Echocardiography, Angiogram or Nuclear Testing.
Time Frame	24 and 52 weeks:

Outcome Measure Data

Analysis Population Description

No analyses were performed due to slow enrollment and early study closure.

Arm/Group Title	No Desensitization	Desensitization
Arm/Group Description	No desensitization therapy pre-transplantation	Plasmapheresis with concomitant bortezomib. Plasmapheresis will be given for 3 consecutive days (treatment days 0, 1 and 2) within 2 weeks of Status I listing for heart transplantation. Plasmapheresis is a procedure that involves the extracorporeal separation of plasma from cellular blood components by centrifugation or membrane filtration, which removes the alloantibody. The plasma depleted blood is reconstituted with exogenous fresh-frozen plasma or albumin solution which is then infused back into the patient. Four doses of bortezomib (1.3 mg/m^2) were administered intravenously on treatment days 0, 3, 7 and 10. The first dose was given between 4-8 hours after the first plasmapheresis session was completed and there was at least 96 hours between the second and third dose of bortezomib
Measure Participants	0	0

15. Secondary Outcome

Title	Incidence of Post-Transplant Lymphoproliferative Disorder (PTLD)
Time Frame	24 and 52 weeks post-transplantation

Outcome Measure Data

Analysis Population Description

No analyses were performed due to slow enrollment and early study closure.

Arm/Group Title	No Desensitization	Desensitization
Arm/Group Description	No desensitization therapy pre-transplantation	Plasmapheresis with concomitant bortezomib. Plasmapheresis will be given for 3 consecutive days (treatment days 0, 1 and 2) within 2 weeks of Status I listing for heart transplantation. Plasmapheresis is a procedure that involves the extracorporeal separation of plasma from cellular blood components by centrifugation or membrane filtration, which removes the alloantibody. The plasma depleted blood is reconstituted with exogenous fresh-frozen plasma or albumin solution which is then infused back into the patient. Four doses of bortezomib (1.3 mg/m^2) were administered intravenously on treatment days 0, 3, 7 and 10. The first dose was given between 4-8 hours after the first plasmapheresis session was completed and there was at least 96 hours between the second and third dose of bortezomib
Measure Participants	0	0

16. Secondary Outcome

Title	Death
Time Frame	24 and 52 weeks post-transplantation

Outcome Measure Data

Analysis Population Description

No analyses were performed due to slow enrollment and early study closure.

Arm/Group Title	No Desensitization	Desensitization
Arm/Group Description	No desensitization therapy pre-transplantation	Plasmapheresis with concomitant bortezomib. Plasmapheresis will be given for 3 consecutive days (treatment days 0, 1 and 2) within 2 weeks of Status I listing for heart transplantation. Plasmapheresis is a procedure that involves the extracorporeal separation of plasma from cellular blood components by centrifugation or membrane filtration, which removes the alloantibody. The plasma depleted blood is reconstituted with exogenous fresh-frozen plasma or albumin solution which is then infused back into the patient. Four doses of bortezomib (1.3 mg/m^2) were administered intravenously on treatment days 0, 3, 7 and 10. The first dose was given between 4-8 hours after the first plasmapheresis session was completed and there was at least 96 hours between the second and third dose of bortezomib
Measure Participants	0	0

17. Secondary Outcome

Title	Re-transplantation or Re-listed for Transplantation
Time Frame	24 and 52 weeks post-transplantation

Outcome Measure Data

Analysis Population Description

No analyses were performed due to slow enrollment and early study closure.

Arm/Group Title	No Desensitization	Desensitization
Arm/Group Description	No desensitization therapy pre-transplantation	Plasmapheresis with concomitant bortezomib. Plasmapheresis will be given for 3 consecutive days (treatment days 0, 1 and 2) within 2 weeks of Status I listing for heart transplantation. Plasmapheresis is a procedure that involves the extracorporeal separation of plasma from cellular blood components by centrifugation or membrane filtration, which removes the alloantibody. The plasma depleted blood is reconstituted with exogenous fresh-frozen plasma or albumin solution which is then infused back into the patient. Four doses of bortezomib (1.3 mg/m2) were administered intravenously on treatment days 0, 3, 7 and 10. The first dose was given between 4-8 hours after the first plasmapheresis session was completed and there was at least 96 hours between the second and third dose of bortezomib
Measure Participants	0	0

18. Secondary Outcome

Title	Incidence of Hospitalizations
Time Frame	24 and 52 weeks post-transplantation

Outcome Measure Data

Analysis Population Description

No analyses were performed due to slow enrollment and early study closure.

Arm/Group Title	No Desensitization	Desensitization
Arm/Group Description	No desensitization therapy pre-transplantation	Plasmapheresis with concomitant bortezomib. Plasmapheresis will be given for 3 consecutive days (treatment days 0, 1 and 2) within 2 weeks of Status I listing for heart transplantation. Plasmapheresis is a procedure that involves the extracorporeal separation of plasma from cellular blood components by centrifugation or membrane filtration, which removes the alloantibody. The plasma depleted blood is reconstituted with exogenous fresh-frozen plasma or albumin solution which is then infused back into the patient. Four doses of bortezomib (1.3 mg/m^2) were administered intravenously on treatment days 0, 3, 7 and 10. The first dose was given between 4-8 hours after the first plasmapheresis session was completed and there was at least 96 hours between the second and third dose of bortezomib
Measure Participants	0	0

19. Secondary Outcome

Title	Incidence of Rejection Episodes Per Subject and Freedom From Rejection
Description	Rejection is defined as follows: Biopsy proven acute rejection (BPAR) of any grade (cellular rejection per 2004 ISHLT [International Society of Heart and Lung Transplantation] grading scale), BPAR (individual grades), BPAR (Biopsy Proven Acute Rejection) > 2R antibody mediated rejection (AMR), Any treated rejection, Rejection associated with hemodynamic compromise (HDC).
Time Frame	24 and 52 weeks post-transplantation

Outcome Measure Data

Analysis Population Description

No analyses were performed due to slow enrollment and early study closure.

Arm/Group Title	No Desensitization	Desensitization
Arm/Group Description	No desensitization therapy pre-transplantation	Plasmapheresis with concomitant bortezomib. Plasmapheresis will be given for 3 consecutive days (treatment days 0, 1 and 2) within 2 weeks of Status I listing for heart transplantation. Plasmapheresis is a procedure that involves the extracorporeal separation of plasma from cellular blood components by centrifugation or membrane filtration, which removes the alloantibody. The plasma depleted blood is reconstituted with exogenous fresh-frozen plasma or albumin solution which is then infused back into the patient. Four doses of bortezomib (1.3 mg/m^2) were administered intravenously on treatment days 0, 3, 7 and 10. The first dose was given between 4-8 hours after the first plasmapheresis session was completed and there was at least 96 hours between the second and third dose of bortezomib
Measure Participants	0	0

Adverse Events

Time Frame	Adverse events were collected from the time of the first protocol mandated procedure until the study completion, or until 30 days after the subject prematurely withdraws from the study.
Adverse Event Reporting Description	The participant randomized to the control arm ("No Desensitization Therapy") completed week 24 (6 months) of post-transplantation evaluations. The participant assigned to the Investigational Arm ("Desensitization Therapy") completed week 52 (12 months) of post-transplantation follow-up.
Arm/Group Title	No Desensitization		Desensitization
Arm/Group Description	No desensitization therapy pre-transplantation		Plasmapheresis with concomitant bortezomib. Plasmapheresis will be given for 3 consecutive days (treatment days 0, 1 and 2) within 2 weeks of Status I listing for heart transplantation. Plasmapheresis is a procedure that involves the extracorporeal separation of plasma from cellular blood components by centrifugation or membrane filtration, which removes the alloantibody. The plasma depleted blood is reconstituted with exogenous fresh-frozen plasma or albumin solution which is then infused back into the patient. Four doses of bortezomib (1.3 mg/m^2) were administered intravenously on treatment days 0, 3, 7 and 10. The first dose was given between 4-8 hours after the first plasmapheresis session was completed and there was at least 96 hours between the second and third dose of bortezomib
All Cause Mortality
	No Desensitization		Desensitization
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	No Desensitization		Desensitization
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/1 (0%)
Other (Not Including Serious) Adverse Events
	No Desensitization		Desensitization
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100%)		0/1 (0%)
Injury, poisoning and procedural complications
compression fracture	1/1 (100%)	1	0/1 (0%)	0

Limitations/Caveats

Study was terminated by the study sponsor, with agreement from the investigators. Reason: very slow rate of accrual and inability to meet the accrual goal within the funding period. (N=2 enrolled. Aim was 80 participants).

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.